This invention relates to compositions which enhance the penetration of pharmaceutically-active agents through the integument. More particularly, this invention relates to free base-acid addition salt combinations of active agents combined with vehicles which facilitate percutaneous and transepidermal delivery of pharmaceutically-active agents.
The resistance of the skin to being penetrated by pharmaceutically-active agents is well documented. As compared to mucosal tissues, the stratum corneum is compact and highly keratinized. The stratum corneum, although relatively thin, is compact and quite impermeable. Such impermeability of the skin is highly essential to the well being of a living organism in that it serves as a barrier to the ingress of pathogens and toxic materials, and the egress of physiologic fluids.
The impermeability of pharmaceutical agents through the skin is due to the nature of the very thin stratum corneum layer which is only 10-15 cells, i.e. about 10 microns thick. This layer is formed naturally by cells migrating toward the skin surface from the basal layer. Cells slowly move from the basal layer to the surface where they are sloughed off. As they progress toward the surface they become progressively more dehydrated and keratinized.
Because of the advantages of dermal application of pharmaceutically-active agents, various penetration enhancers have been sought. A penetration enhancer is generally considered to be one or more compounds which alter the skin as a barrier to increase the flux of a desired pharmaceutical permeant across the skin.
U.S. Pat. No. 4,537,776, Cooper, issued Aug. 27, 1985, contains an excellent summary of prior art and background information detailing the use of certain binary systems for permeant enhancement. Because of the completeness of that disclosure, the information and terminology utilized therein are incorporated herein by reference.
Similarly, European patent application No. 43,738, published Jan. 13, 1982, teaches using selected diols as solvents along with a broad category of cell-envelope disordering compounds for delivery of lipophilic pharmacologically-active compounds. Because of the detail in disclosing the cell-envelope disordering compounds and the diols, this disclosure of European patent application No. 43,738 is also incorporated herein by reference.
A binary system for enhancing metoclopramide penetration is disclosed in UK patent application GB No. 2,153,223 A, published Aug. 21, 1985 and consists of a monovalent alcohol ester of a C8-12 aliphatic monocarboxylic acid (unsaturated and/or branched if C18-32) or a C6-24 aliphatic monoalcohol (unsaturated and/or branched if C14-24) and an N-cyclic compound such as 2-pyrrolidone, N-methylpyrrolidone and the like.
Copending application. Ser. No. 930,764, filed Nov. 14, 1986 is drawn to binary composition consisting of a pharmaceutically-active agent dissolved in or admixed with a penetration-enhancing combination of one or more conventional cell envelope disordering compounds taught in the art cited above and a C2 or C3 alcohol. By using this binary mixture it was found that significant penetration of both hydrophilic and lipophilic permeants could be obtained and was often accompanied by reduced skin irritation.
Other enhancement vehicles, not necessarily associated with binary systems include DMSO or aqueous solutions of DMSO such as taught in Herschler, U.S. Pat. No. 3,551,554; Herschler, U.S. Pat. No. 3,711,602; and Herschler, U.S. Pat. No. 3,711,606, and the azones (n-substituted-alkyl-azacycloalkyl-2-ones) such as noted in Cooper, U.S. Pat. No. 4,557,943.
From the above prior art, it is evident that enhancement of penetration of active agents through the skin has been effected by selecting two primary categories of components, i.e., well-envelope disordering compounds and solvents as the vehicle. While active agents have been categorized as lipophilic or hydrophilic, little attention had been paid to means of manipulating the active agents per se to attain enhanced penetration through the skin barrier. Most prior art teachings are directed to means of enhancing the penetration of active ingredients present in an unionized free base or acid form. Recent examples show some binary enhancement systems enable active ingredients, in their salt form, to penetrate the stratum cornium at rates equal to or less than when in their free base form.